Synthetic Engineering of Bacteriophage for Treatment of Wound Infections

Synthetic Engineering of Bacteriophage for Treatment of Wound Infections

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Antimicrobial resistance in bacterial pathogens is steadily increasing and recognized as one of the greatest threats to global public health. Very few drugs with activity against multidrug-resistant organisms (MDROs) have been brought to market; fewer still are expected in the foreseeable future. Many medical advances that physicians and patients take for granted - including cancer treatment, transplantation, surgery and neonatal care - are endangered by increasing antibiotic resistance and the distressing decline in antibiotic research and development. In addition to more antibacterial drugs, novel and alternative countermeasures are needed.

The initiation of the wars in Afghanistan and Iraq was accompanied by a major increase in wound and healthcare-associated multidrug-resistant infections in the Military Health System (MHS) with extremely limited treatment options. In addition to complicating the care of wounded service members, MDROs have spread to and killed civilian healthcare beneficiaries hospitalized in the same facility as combat casualties. Furthermore, transmission of MDROs has been reported from a war-wounded patient to a healthcare worker resulting in a prolonged, near fatal infection, as well as a similar father/daughter transmission. Many MDROs are resistant to all available antibiotics, making adequate therapy difficult or impossible to achieve. Of particular concern are bacteria called Staphylococcus aureus and Klebsiella pneumoniae commonly found in wound infections that are resistant to methicillin and carbapenem antibiotics.

Therefore, numerous civilian and military agencies and professional societies have called for intensified, novel responses to the antibiotic resistance crisis. The Multidrug-resistant organism Repository and Surveillance Network (MRSN) was established in July 2009 to collect and characterize these organisms across the MHS to inform best clinical practices, influence policy and enhance infection prevention and control efforts. The MRSN has an extensive repository of thousands of isolates from clinical infections obtained from many diverse populations and geographic regions. It has won awards for healthcare innovations.

The focus of this proposed effort will address the FY17 JPC-2/MIDRP ARA focus area to develop and preclinically test novel bacteriophage (phage) biologics as potential therapeutics or prophylactics for the treatment of wound infections and biofilms caused by MDROs. The proposed research will directly impact this focus area through the development and preclinical testing of novel engineered phage drugs to treat or prevent combat-related wound infections caused by K. pneumoniae or S. aureus. Bacteriophages are natural viruses that only infect bacteria and were used before the advent of antibiotics to treat bacterial infections. However, each phage is very specific in that it can only infect and kill certain strains of one bacterial pathogen. We will use modern molecular tools to design phage that have an extended spectrum of infectivity by altering their genome sequence so that they can recognize and kill more strains of MDROs and resist being destroyed by bacterial host defenses. Testing will be performed on collections of bacterial isolates commonly found in wound infections and topical treatment of mice with wound infections.

The successful completion of this project will develop novel phage drugs that could lead to improved prevention and treatment for MDRO infections of current and former Military Service members and other MHS beneficiaries with few treatment options due to the spread of multidrug-resistance. Potential treatments would include topical creams or wound dressings impregnated with the bacteriophage drugs that are developed. In addition, this work could lead to new diagnostic and prevention tools that the MRSN provides to its customers and stake holders. An example new diagnostic tool would be a phage that glows when it detects a specific MDRO, which will provide very sensitive and rapid identification of these pathogenic bacteria. This work will also lead to novel control strategies in the form of new disinfecting agents to remove these MDROs from hospital equipment and surfaces; thus, preventing the risk of the spread of these infection-causing bacteria.

Funding

Funding for this project provided through the Department of Defense Military Infectious Diseases Research Program (MIDRP).